Ординатура / Офтальмология / Английские материалы / Biomaterials and regenerative medicine in ophthalmology_Chirila_2010

Table 4.2 Characteristics of an ideal intracorneal implant system to correct refractive error

∑Transparent material

∑Design should be aimed at a small, thin and flexible lens

∑Optical design should be optimised to be as thin as possible with good edges

∑Permeable material to allow for nutrient flux and nerve regrowth

∑Refractive index of material could match or be different from that of corneal tissue

∑Modulus of material should match that of central corneal tissue

∑Material chemically inactive with low residual extractables and no contaminants

∑Low-fouling material needed to reduce accumulation of proteins, lipids, etc.

∑Biocompatible material should not initiate an inflammatory or immune response

∑Anterior surface treatment to support stable corneal epithelium (onlay)

∑Lens surfaces designed to minimise fibrosis

∑Posterior lens surface treated with adhesive (onlay)

∑Lens design to prevent epithelial undergrowth

∑Lens design to minimise mechanical stresses on cornea

∑Surgical procedure should be quick, minimal and superficial (sub-epithelial if possible)

∑Lens should be easily handled by surgeon

∑Lens should be easy for surgeon to orient right side up

∑Centration of implant should be easy for surgeon

as superficially as possible leaving Bowman’s layer intact to preserve nerves and maintain optimal corneal biomechanics and, most importantly, to confine the wound-healing events to those associated with an epithelial abrasion.

This appears to a very significant factor since penetrating the stroma by any means such as scalpel, microkeratome or laser initiates a stromal woundhealing process that is complicated and prolonged, and is likely to result in opacity or interface haze caused by incomplete healing. Ideally, a synthetic implant placed beneath the epithelium as an onlay is most likely to succeed since an epithelial wound can heal quickly to incorporate the device, offering rapid visual rehabilitation and the opportunity of reversibility. Correction of hyperopia, myopia and presbyopia with this type of approach would deliver breakthrough products to the ophthalmic marketplace.

4.5Corneal repair and replacement

4.5.1The need for materials to repair and replace the cornea

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surface. Corneal blindness is particularly prevalent in less-developed nations where diseases and infections may progress untreated (Garg et al., 2005). Diseased and damaged corneas can be surgically removed and replaced with a button of corneal tissue sourced from cadavers (allografts) in a penetrating keratoplasty procedure. Corneal allografts may be successful and remain clear and provide a successful solution for some, but this is not always the case and recipients may require a second graft or an alternative option. The insufficient number of cadaveric corneas available for transplant is a serious issue and results from the unsuitability of some donated eyes for transplant, the low levels of organ donation due to religious and cultural factors, a lack of general education and the absence of eye-banking facilities, particularly in developing countries. Some ocular surface disorders can now be treated effectively by newer procedures involving the transplantation of biological entities such as autologus limbal stem cells (Tseng, 1989; Kenyon and Tseng, 1989; Dua and Azuara-Blanco, 2000) and/or amniotic membrane (Kim and Tseng, 1995; Park et al., 2008). However, there are many ocular conditions that are recognised as having a ‘high risk of failure’ for the transplant of either corneal grafts or limbal stem cell/amnion approaches and these require an alternative option.

Together, these severe cases have left an unmet clinical need that has driven the development of synthetic corneal replacements. Synthetic devices that replace corneal tissue are known as ‘keratoprostheses’ (KPros) and are used to restore functional visual acuity (and, less commonly, alleviate pain in conditions such as keratopathy) in eyes with severe corneal disease and opacity that carry a poor prognosis for standard corneal transplantation. The ideal keratoprosthesis would be inert and not rejected by the patient’s immune system, it would also be inexpensive and able to maintain longterm clarity. In addition, it would be quick to implant, easy to examine and allow an excellent view of the retina. Section 4.5 examines the history of design approaches to KPros and draws on the knowledge gained from those experiences, noting that each approach has a considerable device history which has been built on in the creation of newer iterations of KPro technologies.

4.5.2Early use of materials as keratoprostheses

The material requirements and design of KPro devices are extremely challenging and have a substantial developmental lineage, which has been well reviewed in several articles (Hicks et al., 1997; Chirila et al., 1998).

Pellier de Quengsy first proposed replacing the cornea with a device made of glass in the eighteenth century and also suggested that the artificial corneal device should have a porous skirt (Chirila et al., 1998; Chirila and Hicks, 1999). In the mid-nineteenth century, this idea was tested when glass was implanted into the eyes of rabbits by Von Nussbaum and Neptuk. Heusser

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KPros. A relatively recent histological evaluation of an eye implanted with a Cardona device showed that PMMA was a suitable material for an optic and had provided good post-operative visual acuity for the 14-year implantation period (Vijayasekaran et al., 2005). The complex skirt area was considered to be predisposed to long-term inflammation. Less complicated surgery and a simple inert device with a flange with good mechanical and biological integration were recommended to reduce post-operative complications (Vijayasekaran et al., 2005).

A slightly different approach was taken in the osteo-odonto-keratoprosthesis

(OOKP) type of KPro originally developed by Strampelli in the 1960s and refined by Falcinelli in the 1970s (Falcinelli et al., 2005; Hille et al., 2005). Like the Cardona and other devices, the OOKP uses PMMA for the transparent optical cylinder and has undergone several design modifications over time. The OOKP has the PMMA optic mounted in a biological support consisting of a longitudinal section of an autologus tooth including some surrounding alveolar bone and ligament with periosteum (Falcinelli et al., 2005; Liu et al., 2005). In the absence of usable teeth, other tissues and matrices of biological origin have been tested such as cartilage (Casey, 1966), tibial bone in the osteo-KPro or Temprano-KPro (Michael et al., 2008) or hydroxyapatite/coral (León et al., 1997). OOKP and osteo-KPro devices are stabilised in the recipient’s cornea by placing autologus buccal mucosa over the top which is opened some time later in a second procedure. These and other penetrating KPros are used to treat end-stage corneal blindness not amenable to penetrating keratoplasty, such as dry keratinised eye resulting from severe Stevens–Johnson syndrome, ocular cicatricial pemphigoid, trachoma and chemical injury resulting in severe corneal scarring leaving the ocular surface keratinised. Falcinelli and co-workers reported good longterm prognosis with the OOKP when they reviewed data from 181 patients implanted between 1973 and 1999 (Falcinelli et al., 2005). Functional and anatomical analysis of the osteo-KPro and OOKP devices showed that both had similar functional results, with the OOKP having slightly better anatomical outcomes; the analysis showed that the difference was influenced more by the status of the retina rather than the actual procedure (Michael et al., 2008). Complications include glaucoma, vitreo-retinal complications, inflammation, epithelial downgrowth and extrusion of the device which is frequently associated with resorption of the biological support (Stoiber et al., 2002). Nonetheless, OOKP is particularly resilient to a hostile environment such as the severely dry eye and is regarded by many as ‘the keratoprosthesis of choice for end-stage corneal blindness not amenable to penetrating keratoplasty’ (Liu et al., 2005; Liu et al., 2008a). Liu has identified the interpentetrating pore network of the alveolar bone used for the biological support to be a key feature in the success of OOKP devices (Liu et al., 2005). Interestingly, coral skeletons that have also shown good outcomes

when tested as biological supports in this type of KPro are reported to have possess a similar pore geometry to dental bone (León et al., 1997).

Dohlman and colleagues used PMMA for the optic of a ‘collar button’- type KPro implanted in patients in 1974. The device, known as the Boston

KPro, has involved a series of design iterations over 30 years, leading to the development of the two currently available versions aimed at full-thickness replacement of the cornea. Both designs require the patient’s crystalline lens to be removed to allow implantation of the KPro. The Boston Type I device is designed for patients with sufficient tear production (wet eyes) and the

Boston Type II is a device for people with ocular pemphigoid and very dry eyes, and is implanted through a closed eyelid (Dohlman and Doane, 1994). The Boston Type 1 KPro was approved by the FDA in 1992 and is the most effective and widely used of these designs. The current version incorporates a rim of donor corneal tissue that is placed over the stem of the front PMMA plate which is clamped and locked with a titanium ring. The periphery of the donor graft tissue is then sutured into the recipient’s cornea, as it would be in a standard corneal graft procedure, and the corneal surface is covered with a soft contact lens. This KPro has shown good outcomes for many patients with non-autoimmune disease and those with previous graft failures who have no other ocular problems. Complications such as inflammation, endophthalmitis, vitritis, glaucoma and retroprosthetic membrane formation do occur and may respond to treatment. Analysis of device failures correlates to pre-operative diagnosis and patients with immune-related disease of the corneal surface are reported to develop inflammation leading to necrosis and melting of the corneal tissue and epithelial downgrowth around the front plate of the device that results in extrusion (Dudenhoefer et al., 2003). Continual modifications to the design in response to problems and new understandings have improved the clinical outcomes for this device over the years of its development (Dohlman and Doane, 1994). The use of biological tissue with the device, in the form of a remnant rim of donor corneal tissue grafted with the device, encourages tissue integration to anchor the device in the cornea. The addition of holes to the PMMA back plate, previously solid, to improve the flow of nutrients from the aqueous humour forward to the grafted corneal tissue has increased the health of the graft and reduced the amount of tissue melt associated with the device (Harissi-Dagher et al., 2007). The application of a soft contact lens to cover the anterior surface of the device and graft tissue post-operatively and continued in the long term has reduced the problem of corneal dehydration and tissue melting around the neck of the device (Harissi-Dagher et al., 2008). Analysis of data from a multicentre study on 210 eyes fitted with the modified Boston Type 1 KPro between 2003 and 2007 showed graft retention rates up to 96% at 8–10 months postoperative, accompanied by vision improvements for 63% of recipients (Zerbe et al., 2006; Belin, 2007). Other problems – such as advanced glaucoma,

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macular degeneration or retinal detachment – were found to be the primary cause of failures (Belin, 2007). The modified Boston Type I KPro may have better outcomes with patients who have had repeated graft failure rather than Stevens–Johnsons syndrome, cicatricial pemphigoid and chemical burns.

4.5.4Keratoprostheses with a synthetic core and skirt

Concurrent activity involving a different KPro design approach utilised a fully synthetic ‘core and skirt’ device made possible by the development of microporous materials. These aimed to reduce the complication rates seen with the use of biological supports by replacing the biological tissue with skirts/haptics made from soft, microporous polymers to assist in the stable integration of the device into the host cornea. Several KPros have been developed on this design principle, some using optical cores made of PMMA which were attached to porous skirts, and other versions using soft hydrogels to create optics and skirts that were fused together to form one-piece devices.

The Seoul-type KPro (S-KPro) used PMMA for the optic in a double-fixed device with a porous flange of polyurethane or polypropylene material for stromal fixation and polypropylene haptics that were sutured to the sclera posterior to the iris to improve device stability. Initial studies (Lee et al., 2000) conducted on the S-KPro involved implantation of the device into

25 rabbit eyes with histology showing that stromal fibroblasts colonised a polyurethane version of the flange/skirt material with a 40 μm pore size over the 2–4 month period of implantation. No retroprosthetic membrane formation was noted during that time, although retinal detachment was a problem and was thought to have been caused by the scleral haptics. Two human subjects, one with chemical burns and one with Stevens–Johnson syndrome, were also implanted with the S-KPro and both devices gave improved vision for the period of retention, which was 8 and 18 months respectively (Lee et al., 2000). These preliminary studies suggested that a porous skirt material could allow biological integration with corneal tissue. Several different porous materials were then compared in rabbits with the best outcomes reported using a polypropylene skirt material (Kim et al., 2002). More recent data from a small group of patients showed that S-KPro devices were retained for an average of 31.6 months, although all suffered from retinal detachments (Kim et al., 2007).

The Pintucci KPro also used a PMMA optic, in this case secured to a soft, pliable skirt made from Dacron (polyethylene terephthalate; PET) fibres, which had an already established track record of use in cardiovascular devices. The porous skirt was designed to encourage integration of new collagen fibres and thus aid integration of the keratoprosthesis into the surrounding ocular tissue. The Pintucci KPro was colonised in the lower lid for 2 months to

allow the porous skirt to populate with autologous fibroblasts; it was then removed and implanted in the cornea and covered with buccal mucosa until stable, and then exposed. Trials of this device in bilaterally blind patients who were unsuitable for corneal transplant showed a range of complications over several years including necrosis of the oral mucosa before exposure of the device, formation of retro-implant membranes, deposit formation, retinal and choroidal detachment, and device extrusion (Pintucci et al., 1995). Some optimisation of the Dacron used in the haptic occurred to further encourage ingrowth of stromal fibroblasts (Pintucci et al., 2001) and developments in the surgical technique used to implant the device have improved the clinical outcomes in patients with vascularised corneas (Pintucci et al., 1996). More recent data from 31 patients blinded with corneal burns, vascularised corneas and dry eye have shown some retention of these devices in patients for up to 6–7 years but not without complications (Maskati and Maskati, 2006). Dacron has been reported to degrade significantly following implantation and this degradation may have contributed to the complications seen in long-term follow-up (Coury et al., 1996). An 85% complication rate after

10 years’ follow-up was reported with the Girard nut and bolt style KPro using a similar Dacron skirt with a PMMA optic (Girard, 1983).

Concurrently, a French group led by Legeais were developing a new KPro device with dimensions similar to the normal cornea which was initially based on a PMMA optic joined to a microporous fluorocarbon skirt made from expanded polytetrafluoroethylene (ePFTE). The haptic was inserted into a stromal lamellar pocket, then a PMMA optic was positioned in a hole made in the central cornea and clipped to the haptic with a PMMA clip and sealing ring which was covered with buccal mucosa for 2 months and then exposed. Implantation of this device did not require the removal of the iris or lens. Trials of this device in a small group of young bilaterally blind patients showed that the microporous skirt was colonised by stromal fibroblasts but the devices were not retained in the long term leading the group to conclude that the biocompatible, inert microporous polymer did not eliminate all of the mechanical complications associated with a KPro (Legeais et al., 1995). The group continued to optimise the ePFTE used as the skirt to encourage stromal integration of the device (Drubaix et al., 1996; Legeais et al., 1997) and the material was also pre-seeded with corneal fibroblasts using a range of chemo-attractants to encourage their ingrowth prior to implantation (Dupuy et al., 2001). The mechanical issues were also addressed by replacement of the rigid PMMA optical core by polydimethylsiloxane (PDMS) coated with polyvinylpyrrolidone and this was fused to the ePTFE skirt in a new one-piece design known as the BioKPro II (Legeais and Renard, 1998). This secondgeneration device was tested in human eyes with some acceptable optical outcomes but resulted in some anatomical failures that involved extrusions, retroprosthetic membranes and endophthalmitis (Legeais and Renard, 1998).

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Legeais recognised that epithelial growth over the anterior surface of the device was essential for the long-term stability of the implant.

A synthetic cornea was also being developed at Boston University (Trinkaus-

Randall group) using a transparent, flexible polyvinylalcohol (PVA) hydrogel with a refractive index of 1.42 which was bonded to a fibrous skirt of blown microfibre polybutylene and polypropylene (Tsuk et al., 1997). The design of this KPro was strongly driven by an understanding of corneal biology, with the surface of the PVA optic plasma modified to encourage the growth of epithelial tissue, which occurred without any added biological coating when tested in an organ culture system (Latkany et al., 1997). Devices were pre-seeded with stromal fibroblasts and epithelial cells to create a three- dimensional construct. Various iterations of these devices were implanted into rabbit corneas using different surgical procedures which resulted in partial epithelialisation of the surfaces at 3 weeks post-operative (Trinkaus-Randall et al., 1997). Controlled release technology was also incorporated into the skirt to deliver growth factors aimed at promoting anchorage by increasing fibroplasia (Trinkaus-Randall and Nugent, 1998) and alternative materials were tested to improve the function of the skirt (Wu et al., 1998). This work acknowledged the need for fibrous ingrowth for anchorage and also identified the need for epithelialisation of the anterior surface of a synthetic cornea but overall it failed to provide a long-term solution as a synthetic cornea.

Concurrent activity at the Lions Eye Institute and Centre for Ophthalmology and Visual Science in Perth in Western Australia (Chirila group) gave rise to a new design concept and material approach that involved a one-part, fused ‘core-and-skirt’ KPro. Both the core and skirt were made of the same soft, hydrogel material, PHEMA, that was prepared slightly differently to produce a transparent optical core that was fused to an opaque, macroporous peripheral skirt intended to promote anchorage of the device in the stromal tissue (Chirila et al., 1993; Chirila et al., 1994). Originally known as the Chirila KPro, this device was eventually marketed as the AlphaCor KPro (first by Argus Biomedical in Perth Australia, then by CooperVision in the USA, and now by Addition Technologies Inc., Des Plaines, Illinois, USA). It offered several advantages over competitive technologies at the time. It was a one-part device that could be sutured in place in a relatively simple procedure and in this sense was truly a synthetic corneal graft. The initial design version was sutured in place and covered with conjunctival tissue which was opened in a second procedure some months later. The later version was slightly smaller than the original and was implanted into a lamellar pocket with its posterior face removed and the anterior surface of the device covered by a corneal tissue and a conjunctival flap, which again was opened some months later. Early data arising from devices implanted in rabbit and human corneas demonstrated the potential of the AlphaCor technology (Hicks et al., 1998; Hicks et al., 2000; Hicks et al., 2003). Later trials with 337 carefully

selected patients showing retention rates of 80% at 1 year and 62% at 2 years (Hicks et al., 2006). Over 300 AlphaCor devices have been implanted to date and followed for up to 7 years (Liu et al., 2008a). The retention rates may be attributed to the porous nature of the KPro skirt, optimised during the design phase for fibroblastic ingrowth to anchor the device (Vijayasekaran et al., 1998), which showed the presence of stromal fibroblasts and new collagen formation within the porous pHEMA material when explanted and examined histologically (Hicks et al., 2005). Complications of the AlphaCor KPro include stromal melting and white deposits within the optical core (Hicks et al., 2006), with topical medications used in conjunction with the AlphaCor

KPro found to have contributed to the white calcium deposits (Vijayasekaran et al., 2000; Hicks et al., 2004). Cigarette smoke was identified as the cause of brown pigmentation noted in other AlphaCor implants (Hicks et al., 2004) revealing the unexpected impact that environmental factors might have on KPro devices. Stromal melting has historically been recognised as a major problem with all KPro devices and is mediated by matrix metalloproteases that digest corneal stromal collagens. Melting associated with the AlphaCor KPro was addressed using topical treatment with medroxyprogesterone in some patients and data compared against those who were not treated. Outcomes showed the incidence of melting increased if medroxyprogesterone was used, but its use delayed the onset of the melting process (Hicks and Crawford, 2003). A more recent study of three patients implanted with AlphaCor devices which failed owing to stromal melting, used immunohistochemistry to show that fibroblasts that colonised the skirt to achieve biointegration were activated and transformed into a contractile, myofibroblast phenotype that was identified as a likely source of pro-inflammatory cytokines associated with stromal melting (Coassin et al., 2007). These outcomes suggest that there might be an inadequate flux through the material causing tissue necrosis by nutritional deprivation of tissue forward of the implant. It is possible that the material used in the AlphaCor device may be slowly fouling, causing a progressive reduction of permeability with time. PHEMA hydrogels are recognised to be prone to calcification and, although the causes of this are not fully understood, their porous nature inherently creates surface defects which have been shown to increase the tendency for calcification (Lou et al., 2005). Different techniques that simplified the surgical procedure used to implant the AlphaCor device, with the aim of reducing the surgical trauma, appear to have failed to improve the outcomes of this KPro device.

4.5.5Overall outcomes on materials and devices for corneal repair and replacement